title: Surface coatings that promote rapid release of peptide-based AgrC inhibitors for attenuation of quorum sensing in Staphylococcus aureus.
abstract: Staphylococcus aureus is a major human pathogen responsible for a variety of life-threatening infections. The pathogenicity of this organism is attributed to its ability to produce a range of virulence factors and toxins, including the superantigen toxic shock syndrome toxin-1 (TSST-1). While many S. aureus infections can be treated using conventional antibiotics, strains resistant to these bactericidal agents have emerged. Approaches that suppress pathogenicity through mechanisms that are nonbactericidal (i.e., antivirulence approaches) could provide new options for treating infections, including those caused by resistant strains. Here, we report a nonbactericidal approach to suppressing pathogenicity based on the release of macrocyclic peptides (1 and 2) that inhibit the agr quorum sensing (QS) circuit in group-III S. aureus. It is demonstrated that these peptides can be immobilized on planar and complex objects (on glass slides, nonwoven meshes, or within absorbent tampons) using the rapidly dissolving polymer carboxymethylcellulose (CMC). Peptide-loaded CMC films released peptide rapidly (<5 min) and promoted strong (>95%) inhibition of the agr QS circuit without inducing cell death when incubated in the presence of a group-III S. aureus gfp-reporter strain. Peptide 1 is among the most potent inhibitors of QS in S. aureus reported to date, and the group-III QS circuit regulates production of TSST-1, the primary cause of toxic shock syndrome (TSS). These results thus suggest approaches to treat the outer covers of tampons, wound dressings, or other objects to suppress toxin production and reduce the severity of TSS in clinical and personal care contexts. Because peptide 1 also inhibits QS in S. aureus groups-I, -II, and -IV, this approach could also provide a pathway for attenuation of QS and associated virulence phenotypes in a broader range of contexts.
authors.affiliation: Department of Chemical and Biological Engineering, 1415 Engineering Drive, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Adam H
authors.initials: AH
authors.lastname: Broderick
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Stacy
authors.forename: Yftah
authors.initials: Y
authors.lastname: Tal-Gan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kratochvil
authors.forename: Helen E
authors.initials: HE
authors.lastname: Blackwell
authors.forename: David M
authors.initials: DM
authors.lastname: Lynn
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D011494:Protein Kinases / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects; D013211:Staphylococcus aureus / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D001426:Bacterial Proteins; D010455:Peptides; D011108:Polymers; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus; D002266:Carboxymethylcellulose Sodium
keywords: antivirulence; drug delivery; nonbactericidal; surface coatings; toxic shock